Risk Evaluation in HCM Temporal Repolization lability in HCM Caused by Beta-Myosin Heavy Chain Gene (MHY7) Mutations: Certain genetic mutations in HCM carry increased risk of sudden death. We measured the QT variability index (QTVI) and heart rate-QT interval coherence in 36 patients with HCM caused by 7 MHY7 mutations and in 26 age- and sex- matched controls. QTVI was higher and coherence was lower in HCM patients than controls. The greatest abnormalities were detected in patients with the malignant R403Q mutation. Our findings suggest that HCM caused by MHY7 mutations exhibits labile repolarization quantified by QTVI analysis, and hence, may be associated with increased risk for sudden death from ventricular arrhythmias. Role of Electrophysiologic (EP) and Other Studies in Children with HCM: In an ongoing evaluation we are studying the ability of EP study and exercise thallium scintigraphy to predict cardiac events in about 100 children with HCM. Myocardial Bridging in HCM: We examined the recently reported association of coronary artery bridging, in HCM children and severity of the disease, risk of arrhythmias and sudden death. Bridging was present in 23 of 57 (52 per cent) children. Bridging involved the left anterior descending artery (LAD) in 21 of 31 (68 per cent) affected vessels. Myocardial perfusion abnormalities were present in 7 of 19 (37 per cent) children without bridging and in 15 of 17 (88 per cent) children with bridging. However, bridging was associated with more severe septal hypertrophy, a higher septum:post wall thickness ratio, and higher left ventricular (LV) outflow gradient. Multivariate analysis demonstrated that LV wall thickness, and not bridging, was an independent predictor of thallium perfusion abnormalities. Bridging was also not associated with significantly greater symptoms, increased QT and QTc intervals and QTc dispersion, or ventricular tachycardia on Holter or induced at EP study. Survival was similar in children with and without bridging. Compression of septal LAD branches was present in 27 (61 per cent) of the children and was significantly associated with bridging, severity of LV hypertrophy and LV outflow obstruction. We conclude that bridging is common in HCM children and is related to magnitude of LV hypertrophy and outflow obstruction. The myocardial perfusion abnormalities reflect the severity of the LV hypertrophy. Our findings therefore suggest that bridging is not an important cause of myocardial ischemia, ventricular arrhythmias or sudden death in HCM children. Long-Term Results of DDD Pacemaker Therapy in Adult Patients with Obstructive HCM: As an alternative to cardiac surgery, we have studied the ability of pacemaker therapy to improve severe drug- refractory symptoms and relieve LV outflow obstruction in patients in whom the LV hypertrophy results in intra-cavitary obstruction. The evidence indicates that the hemodynamic and symptomatic benefits of this novel therapy are maintained 5 years after pacemaker insertion. Double-Blind Placebo-Controlled Study of Discontinuing AV Pacing After Prolonged Pacemaker Therapy: In this study, half of the patients were maintained on DDD pacing but AV pacing was programmed off in the remaining patients. Exercise tests and indices of LV outflow obstruction were re-measured after 6 months. LV ouflow obstruction did not recur in all but one patient. The findings provide further evidence for cardiac adaptive changes and remodeling in response to prolonged pacing. Negative Hystereisis Dual Chamber (DDD) Pacemaker Device: Appropriate pacemaker programming is critical to the success of pacemaker therapy for obstructive HCM. In an ongoing study we examine the ability of a special DDD pacemaker that autoregulates its programming to improve management of obstructive HCM. DDD Pacemaker Therapy in Children with Obstructive HCM: Severity of obstructive hypertrophic cardiomyopathy (HCM) increases in children but there is no uniform opinion as to its management. Therapeutic options include pharmacotherapy, cardiac surgery and transplantation. A preliminary analysis of a study of children with obstructive HCM treated with DDD pacing has demonstrated that one or more clinical features associated with increased risk for sudden death were present in most of the study children. Exercise duration was less than 10th percentile predicted for age/gender in about two-thirds of the children at baseline compared to 40 per cent at the last follow-up evaluation. The increase in exercise durations was also significant: 639+/-164 minutes versus 530+/-179 minutes. At a cardiac catheterization performed at a mean follow-up period of 25+/-1 months the LV gradient had reduced from 77+/-47 mm Hg to 37+/-32 mm Hg. LV filling pressures were not changed significantly. RV outflow obstruction was present in 40 per cent of the children. At the final follow-up study, the RV gradient was significantly less: 5+/- 4 mm Hg vs 10+/-11 mm Hg. Two sudden deaths have occurred during a follow-up period of 43+/-12 months: an annual sudden death-rate of 1.8 per cent. A further child died postoperatively, following defibrillator implantation, and 4 underwent cardiac surgery. The results of this uncontrolled study suggest that dual chamber (DDD) pacing reduces intracavitary obstruction and significantly improves exercise performance in most of HCM children during a period of rapid body growth. Randomized Cross-over study of DDD Pacemaker Therapy in Symptomatic Children with Obstructive HCM: We have initiated a randomized, cross-over study of DDD pacing versus placebo (AAI pacing mode) in children who have limited exercise performance +/- symptoms despite medical therapy (beta-blocker +/-verapamil). Study subjects receive a pacemaker and are randomized to one of two pacing modes (DDD, AAI). After a 1-year follow-up evaluation the children cross-over to the alternative pacing mode, and are re-evaluated after a further year. All children continue to receive optimum medical therapy (beta-blocker or verapamil) based on improvement in symptoms and exercise performance. The subjects undergo outpatient evaluations (exercise tests and echocardiography)6 & 18 months after pacemaker implantation, and inpatient evaluations (exercise tests, echocardiography, and cardiac catheterization) 1 year and 2 years after entry into the study. Primary end-points are exercise duration and severity of LV outflow obstruction. The patient, parents, referring physician, and individual supervising the exercise tests are blinded to the pacing mode. A Randomized Prospective Comparison of DDD Pacing & Percutaneous Transluminal Septal Ablation (PTSA)in Obstructive HCM Associated With Severe Drug-Refractory Symptoms: Patients with obstructive HCM and drug-refractory symptoms are referred for cardiac surgery. DDD pacemaker therapy and PTSA have been proposed as alternative therapies tp cardiac surgery. PTSA involves infusion of ethanol via an angioplasty catheter into one or more septal perforator branches of the LAD artery. The aim is to infarct and thereby thin the part of the proximal interventricular septum that is implicated in the LV outflow obstruction. Preliminary studies have reported a 70 per cent reduction in LV pressure gradients, and significant improvement of symptoms and exercise tolerance. PTSA has been generally well tolerated. However, it has been complicated by in-hospital conduction abnormalities and heart block requiring pacemaker implantation, ventricular arrhythmias, and death. The late results of this procedure are unknown. Potential adverse long term consequences of PTSA may include late arrhythmias and LV dysfunction, although these complications have not been reported. It is also possible that as with cardiac surgery, the LV dysfunction due to the PTSA is compensated for by a reduced LV work load that results from the lower LV systolic pressures and relief of the LV outflow obstruction. Unfortunately, studies assessing PTSA have often provided incomplete hemodynamic data, or have been performed on drugs that affect LV outflow pressure gradients. There is therefore an important need for more rigorous studies assessing the efficacy of PTSA and to compare the results of this therapy with DDD pacing. Our study compares the results of DDD pacing and PTSA in a randomized fashion in 70 patients with obstructive HCM and severe symptoms refractory to standard drug therapy. Treatment of Mid-Ventricular Obstructive Cardiomyopathy With PTSA: Resolution of LV Aneurysm Following Relief of Intra- Ventricular Pressure Gradient: In patients with mid-ventricular HCM the obstruction is at the level of markedly hypertrophied papillary muscles. There is often a distal LV aneurysm believed to result from apical infarction and scarring, and affected patients are prone to congestive heart failure and arrhythmia. Mid-ventricular HCM often presents a difficult therapeutic challenge. We evaluated the ability of PTSA to treat mid- ventricular obstructive HCM associated with drug- refractory symptoms in 3 patients. Intra-coronary artery echo-contrast imaging was used to identify septal perforators to be ablated. PTSA was uncomplicated. In all 3 patients PTSA reduced LV apical systolic pressures, intra-cavitary LV pressure gradients, and pulmonary artery capillary wedge pressures, and increased systemic arterial pulse pressure. Notably, in a patient with a large LV aneurysm, elimination of the mid-cavity obstruction was associated with resolution of the apical aneurysm, and normal contraction and thickening of the distal segment. PTSA was not complicated by mitral regurgitation. Hence, PTSA may be an effective therapy in this rare but important subset of patients with obstructive HCM. The distal LV aneurysm in mid-LV HCM may consist of viable myocardium, and is potentially versible.